Handbook of ReagentsHandbook of Reagents for Organic Synthesis Catalyst Components for Coupling...

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Handbook of Reagents

for Organic Synthesis

Catalyst Components forCoupling Reactions

OTHER TITLES IN THIS COLLECTION

Fluorine-Containing Reagents

Edited by Leo A. Paquette

ISBN 978 0 470 02177 4

Reagents for Direct Functionalization for C–H Bonds

Edited by Philip L. Fuchs

ISBN 0 470 01022 3

Reagents for Glycoside, Nucleotide, and Peptide Synthesis

Edited by David Crich

ISBN 0 470 02304 X

Reagents for High-Throughput Solid-Phase and Solution-Phase

Organic Synthesis

Edited by Peter Wipf

ISBN 0 470 86298 X

Chiral Reagents for Asymmetric Synthesis

Edited by Leo A. Paquette

ISBN 0 470 85625 4

Activating Agents and Protecting Groups

Edited by Anthony J. Pearson and William R. Roush

ISBN 0 471 97927 9

Acidic and Basic Reagents

Edited by Hans J. Reich and James H. Rigby

ISBN 0 471 97925 2

Oxidizing and Reducing Agents

Edited by Steven D. Burke and Rick L. Danheiser

ISBN 0 471 97926 0

Reagents, Auxiliaries and Catalysts for C–C Bond Formation

Edited by Robert M. Coates and Scott E. Denmark

ISBN 0 471 97924 4

e-EROS

For access to information on all the reagents covered in theHandbooks of Reagents for Organic Synthesis, and many more,

subscribe to e-EROS on the Wiley Interscience website.A database is available with over 200 new entries and updates everyyear. It is fully searchable by structure, substructure and reaction

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Handbook of Reagents

for Organic Synthesis

Catalyst Components forCoupling Reactions

Edited by

Gary A. MolanderUniversity of Pennsylvania, Philadelphia, PA, USA

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Handbook of reagents for organic synthesis.p. cm.

Includes bibliographical references.Contents: [1] Reagents, auxiliaries, and catalysts for C–C bond formation/edited by Robert M.Coates and Scott E. Denmark [2] Oxidising and reducing agents/edited by Steven D. Burke and RiekL. Danheiser [3] Acidic and basic reagents/edited by Hans J. Reich and James H. Rigby [4]Activating agents and protecting groups/edited by Anthony J. Pearson and William R. Roush [5]Chiral Reagents for Asymmetric Synthesis/edited by Leo A. Paquette [6] Reagents for high-throughput solid-phase and solution-phase organic synthesis / edited by Peter Wipf [7] Reagentsfor glycoside, nucleotide and peptide synthesis / edited by David Crich [8] Reagents for directfunctionalization of C–H bonds/edited by Philip L. Fuchs [9] Fluorine-Containing Reagents/editedby Leo A. Paquette [10] Catalyst Components for Coupling Reactions / edited by Gary A.Molander

ISBN 0-471-97924-4 (v. 1) ISBN 0-471-97926-0 (v. 2)ISBN 0-471-97925-2 (v. 3) ISBN 0-471-97927-9 (v. 4)ISBN 0-470-85625-4 (v. 5) ISBN 0-470-86298-X (v. 6)ISBN 0-470-02304-X (v. 7) ISBN 0-470-01022-3 (v. 8)ISBN 978-0-470-02177-4 (v. 9) ISBN 978-0-470-51811-3 (v.10)

1. Chemical tests and reagents. 2. Organic compounds–Synthesis.QD77.H37 1999 98-530885470.2 dc 21 CIP

British Library Cataloguing in Publication DataA catalogue record for this book is available from the British Library

ISBN 13: 978-0-470-51811-3 (Hb)

Typeset in 9½/11½ pt Times Roman by Thomson Press (India) Ltd., New Delhi.Printed and bound in Great Britain by Antony Rowe, Chippenham, WiltshireThis book is printed on acid-free paper responsibly manufactured from sustainable forestryin which at least two trees are planted for each one used for paper production.

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e-EROS Editorial Board

Editor-in-Chief

Leo A. Paquette

The Ohio State University, Columbus, OH, USA

Executive Editors

David Crich

Wayne State University, Detroit, MI, USA

Philip L. Fuchs

Purdue University, West Lafayette, IN, USA

Gary Molander

University of Pennsylvania, Philadelphia, PA, USA

Contents

Preface ix

Introduction xi

Recent Review Articles and Monographs 1

1-Adamantyl-di-tert-butylphosphine 5

Benzylchlorobis(triphenylphosphine)palladium(II) 7

[1,10-Biphenyl]-2-yldicyclohexylphosphine 8

Bis(acetonitrile)[(1,2,5,6-�)-1,5-cyclooctadiene]-rhodium(1þ),tetrafluoroborate(1-) 12

Bis(acetonitrile)dichloropalladium(II) 15

Bis(allyl)di-�-chlorodipalladium 31

(R,R)-1,2-Bis(aminocarbonylphenyl-20-diphenylphosphino)cyclohexane 54

Bis(benzonitrile)dibromopalladium(II) 59

Bis(benzonitrile)dichloropalladium(II) 60

Bis(bicyclo[2.2.1]hepta-2,5-diene)dichlorodirhodium 84

Bis[(1R)-[1,10-binaphthalene]-2,20-diylbis[diphenyl-phosphine-�P]]di-�-hydroxydirhodium 88

Bis[1,2-bis(diphenylphosphino)ethane]palladium(0) 90

[[2,6-Bis[[(bis(1-methylethyl)phosphino-P]methyl]-3,5

dimethylphenyl]methyl-C]trifluoroacetato-O)palladium 91

Bis[(1,2,5,6-�)-1,5-cyclooctadiene]di-�-hydroxydirhodium 92

Bis[(1,2,5,6-�)-1,5-cyclooctadiene]di-�-methoxydirhodium 94

Bis(1,5-cyclooctadiene)nickel(0) 95

Bis[(1,2,5,6-�)-1,5-cyclooctadiene] rhodium(1þ),

Hexafluoroantimonate(1�) 114

Bis(dibenzylideneacetone)palladium(0) 118

1,3-Bis(2,6-diisopropylphenyl)-4,5-dihydroimidazol-

2-ylidene 124

1,3-Bis(2,6-diisopropylphenyl)-imidazol-2-ylidene 126

Bis(1,1-dimethylethyl)[20,40,60-tris(1-methylethyl)[1,10-biphenyl]-2-yl]phosphine and Dicyclohexyl[20,40,60-tris(1-methylethyl)[1,10-biphenyl]-2-yl]phosphine 127

(R)- & (S)-2,20-Bis(diphenylphosphino)-1,10-binaphthyl 130

1,4-Bis(diphenylphosphino)butane 141

(2R,3R)-2,3-Bis(diphenylphosphino)butane 142

1,2-Bis(diphenylphosphino)ethane 144

1,10-Bis(diphenylphosphino)ferrocene 146

Bis[2-(diphenylphosphino)phenyl]ether (DPE-phos) 155

1,3-Bis(diphenylphosphino)propane 161

Bis(�2-ethene)(2,4-pentanedionato-O,O0) rhodium 163

Bis(triphenylphosphine)[1,2-bis(diphenylphosphino)-

ethane]palladium(0) 165

Bis(triphenylphosphine)nickel(0) 167

Bis(triphenylphosphine)palladium(II) acetate 168

Bis[tri(o-tolyl)phosphine]palladium 173

Bromo(o-tolyl)bis(triethylphosphine)nickel(II) 182

1-Butyl-3-methylimidazolium Hexafluorophosphate

([Bmim]PF6) 182

(R,S)-CAMPHOS 189

Carbonyl(chloro)bis(triphenylphosphine)rhodium(I) 190

Chloro(1,5-cyclooctadiene)rhodium(I) Dimer 199

Chlorotris(triphenylphosphine)rhodium(I) 206

Cobalt(II) Chloride 218

Copper 222

Copper(II) Acetate 226

Copper(II) Acetylacetonate 232

Copper(I) Bromide 235

Copper Bronze 242

Copper(II) Chloride 243

Copper(I) Chloride-Oxygen 250

Copper(II) Hydroxide 264

Copper(I) Iodide 264

Copper(I) Iodide–Potassium Naphthalenide 275

Copper(I) Iodide–Triethyl Phosphite 275

Copper(I) Oxide 276

Copper(I) Trifluoromethanesulfonate 281

[(1R,2R,3S,4S)-1,2,3,4-Cyclopentanetetrakis(methylene)]-

tetrakis[diphenyl]phosphine 303

Diacetatobis(tri-o-tolylphosphine)palladium(II) 307

Dibromobis(triphenylphosphine)nickel(II) 307

Dibromobis(triphenylphosphine)palladium(II) 309

2-(Di-tert-butylphosphino)biphenyl 310

Dicarbonyl(acetylacetonato) rhodium(I) 314

Dichloro[1,4-bis(diphenylphosphino)butane]nickel(II) 316

Dichloro[1,4-bis(diphenylphosphino)butane]palladium(II) 318

Dichloro[1,2-bis(diphenylphosphino)ethane]palladium(II) 320

Dichloro[1,10-bis(diphenylphosphino)ferrocene]-palladium(II) 321

Dichlorobis(tricyclohexylphosphine)palladium 322

Dichlorobis(triphenylphosphine)nickel(II) 326

Dichlorobis(triphenylphosphine)palladium(II) 332

Dichlorobis(tri-o-tolylphosphine)palladium(II) 343

Dichloro[2,3-O-isopropylidene-2,3-dihydroxy-1,4-bis-

(diphenylphosphino)butane]palladium(II) 345

Dicyclohexyl(20,60-dimethoxy[1,10-biphenyl]-2-yl)-phosphine (S-Phos) 346

2-Dicyclohexylphosphino-20-(N,N-dimethylamino)-

biphenyl 348

(R)-1-[(1R)-1-(Dicyclohexylphosphino)ethyl]-2-

(diphenylphosphino)-ferrocene, (2S)-1-[(1R)-1-

(Dicyclohexylphosphino)ethyl]-2-(diphenylphosphino)-

ferrocene, (Josiphos) 353

2-(20-Dicyclohexylphosphinophenyl)-2-methyl-

1,3-dioxolane 364

1-(4,5-Dihydro-4-phenyl-2-oxazolyl)-2-(diphenyl-

phosphino) ferrocene 365

(1,3-Diisopropylimidazol-2-ylidene)(3-chloropyridyl)

palladium(II) chloride (PEPPSI) 367

Dilithium Tetrachlorocuprate(II) 370

Dilithium Tetrachloropalladate(II) 375

(R)-N-[2-(N,N-Dimethylamino)ethyl]-N-methyl-1-[(S)-10,2-bis(diphenylphosphino)ferrocenyl]ethylamine 377

(R)-N,N-Dimethyl-1-[(S)-2-(diphenylphosphino)ferrocenyl]-

ethylamine 380

(4S)-4-(1,1-Dimethylethyl)-2-1-[(11bS)dinaphtho-

[2,1-d:10,20f][1,3,2]-dioxaphosphepin-4-yloxy]-1-methylethyl-4,5-dihydrooxazole 381

(1R,2S,4R,5S)-2,5-Dimethyl-7-phenyl-7-phosphabi-

cyclo[2.2.1]heptane 384

(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis[diphenyl-

phosphine (Xantphos) 385

20-(Diphenylphosphino)-N,N-dimethyl[1,10-binaphthalen]-2-amine 387

(S)-2-[2-(Diphenylphosphino)phenyl]-4-phenyloxazoline 391

Encapsulated Palladium Catalysts 403

Hydrotetrakis(triphenylphosphine)rhodium 409

Iodo(phenyl)bis(triphenylphosphine)palladium(II) 413

Iron(III) Chloride 414

Lithium Trichloropalladate 423

(Maleic anhydride)bis(triphenylphosphine)palladium 425

Merrifield-diphenylphosphine Palladium Complexes 430

Nickel 435

Nickel(II) Acetylacetonate 436

Nickel(II) Bromide 442

Nickel-in-Charcoal (NiII/C) 444

Nickel(II) Chloride 447

(R,R)-(�)-NORPHOS, (S,S)-(þ)-NORPHOS 451

Palladium(II) Acetate 459

Palladium(II) Acetylacetonate 483

Palladium(II) Chloride 484

Palladium(II) Chloride–Silver(I) Acetate 502

Palladium–Graphite 502

Palladium Nanoparticles 503

Palladium(II) Trifluoroacetate 515

1,2,3,4,5-Pentaphenyl-10-(di-tert-butylphosphino)ferrocene (Q-Phos) 516

Potassium Tetrachloropalladate(II) 519

Proazaphosphatranes 523

Silver(I) Oxide 527

Tetrakis(acetonitrile)copper(I) Perchlorate 533

Tetrakis(acetonitrile)copper(I) Tetrafluoroborate 537

Tetrakis(acetonitrile)palladium Tetrafluoroborate 542

Tetrakis(triisopropyl phosphite)palladium(0) 547

Tetrakis(triphenylphosphine)nickel(0) 548

Tetrakis(triphenylphosphine)palladium(0) 550

Tri-tert-butylphosphine 559

Tri-tert-butylphosphine Tetrafluoroborate 562

Tricyclohexylphosphine 566

Tri-2-furylphosphine (TFP) 569

Trimethyl Phosphite 576

Triphenylarsine 582

Triphenyl Phosphite 587

Tris(acetoacetonyl)cobalt 593

Tris(acetonitrile)tricarbonyltungsten 595

Tris(acetylacetonato)iron(III) 596

Tris(dibenzoylmethide)iron(III) 600

Tris(dibenzylideneacetone)dipalladium–Chloroform 602

Tris(triphenylphosphine)nickel(0) 607

m-Trisulfonated Triphenylphosphine 609

Tri-o-Tolylphosphine 620

Zinc/Nickel Couple 625

List of Contributors 627

Reagent Formula Index 639

Subject Index 643

viii CONTENTS

General Abbreviations

Preface

As stated in its preface, the major motivation for our

undertaking the publication of the Encyclopedia of Reagents

for Organic Synthesiswas ‘‘to incorporate into a single work a

genuinely authoritative and systematic description of the

utility of all reagents used in organic chemistry.’’ By all

accounts, this reference compendium succeeded admirably in

approaching this objective. Experts from around the globe

contributed many relevant facts that define the various uses

characteristic of each reagent. The choice of a masthead

format for providing relevant information about each entry, the

highlighting of key transformationswith illustrative equations,

and the incorporation of detailed indexes serve in tandem to

facilitate the retrieval of desired information.

Notwithstanding these accomplishments, the editors came

to recognize that the large size of this eight-volume work and

prohibitive cost often deterred the placement of copies of the

Encyclopedia in or near laboratories where the need for this

type of information is most critical. In an effort to meet this

demand in a cost-effective manner, the decision was made to

cull from the major work that information with the highest

probability for repeated consultation and to incorporate the

same into a set of handbooks. The latter would also be

purchasable on a single unit basis.

The ultimate result of these deliberations was the

publication of the Handbook of Reagents for Organic

Synthesis, the first four volumes of which appeared in 1999:

Reagents, Auxiliaries and Catalysts for C–C BondFormationEdited by Robert M. Coates and Scott E. Denmark

Oxidizing and Reducing AgentsEdited by Steven D. Burke and Rick L. Danheiser

Acidic and Basic ReagentsEdited by Hans J. Reich and James H. Rigby

Activating Agents and Protecting GroupsEdited by Anthony J. Pearson and William R. Roush

Since then, the fifth, sixth, seventh, eighth, and ninth members

of this series listed below have made their appearance:

Chiral Reagents for Asymmetric SynthesisEdited by Leo A. Paquette

Reagents for High-Throughput Solid-Phase andSolution-Phase Organic SynthesisEdited by Peter Wipf

Reagents for Glycoside, Nucleotide, and PeptideSynthesisEdited by David Crich

Reagents for Direct Functionalization of C–H BondsEdited by Philip L. Fuchs

Fluorine-Containing ReagentsEdited by Leo A. Paquette

Each of thevolumes contains a selected compilation of those

entries from the original Encyclopedia that bear on the

specific topic. The coverage of the last five handbooks also

extends to the electronic sequel e-EROS. Ample listings can

be found to functionally related reagents contained in the

original work. For the sake of current awareness, references to

recent reviews and monographs have been included, as have

relevant new procedures from Organic Syntheses.The present volume, entitled Catalyst Components for

Coupling Reactions, constitutes the tenth entry in a

continuing series of utilitarian reference works. As with its

predecessors, this handbook is intended to be an affordable,

enlightening compilation that will hopefully find its way into

the laboratories of all practicing synthetic chemists. Every

attempt has been made to be of the broadest possible relevance

and it is hoped that our colleagues will share this opinion.

Leo A. PaquetteDepartment of Chemistry

The Ohio State University

Columbus, OH, USA

Introduction

Among the myriad new methodological strategies devel-

oped over the past 50 years, none has impacted the

construction of organic molecules as much as those

transformations categorized as cross-coupling reactions.

From the synthesis of pharmacologically active agents and

natural products to all manner of new materials, the various

synthetic methods established under the cross-coupling

umbrella have revolutionized the manner in which novel

molecular architectures are assembled. Recognizing the

well-known limitations of classical SN1 and SN2 reactions,

in the 1970s chemists began their search for catalyzed

reactions that were able to overcome the energy barriers to

substitution at sp- and sp2-hybridized centers. Most of the

processes derived from these investigations rapidly assumed

their current status as ‘‘name reactions,’’ including the

Suzuki–Miyaura, Negishi, Kumada–Tamao/Corriu, Stille/

Migita–Kosugi, Tamao–Kumada/Hiyama–Hatanaka, and

Sonogashira cross-couplings, as well as the Mizoroki–Heck,

Tsuji–Trost, and Buchwald–Hartwig reactions.Each of these cross-coupling processes is associated with a

different set of reagents (e.g., organoborons, organozincs, etc.)

that are vast in their scope and thus difficult to assemble in

reasonable encyclopedic form. However, all cross-couplings are

inextricably linked by one common theme—they employ catalyst

systems comprised of various metal complexes and ligands that

promote the reactions through catalytic cycles in which many of

the individual steps are identical or related by analogy. As a

consequence, familiarity with the properties and capabilities of

the various catalyst components in one regime often opens diverse

opportunities for application across the entire spectrum of cross-

coupling transformations. For this reason, the current volume

serves as a departure from its progenitors in that it focuses not on

specific reagents, but rather on the individual components of

catalyst systems.

The various precatalysts, catalysts, and ligands highlighted

herein were selected from three different sources. The first set of

these ‘‘reagents’’ appeared in the original Encyclopedia of

Reagents for Organic Synthesis (EROS), which was published

in 1995. Importantly, the vast majority of these have been

subsequently updated by leading experts and appear in the

continually expanding online encyclopedia eEROS. This supple-

mental information, so critical in the rapidly developing field of

cross-coupling, is found herein in the form of extensions to the

original article. Finally, entirely new compounds to EROS, again

contributed by skilled practitioners in the art who have outlined

the latest developments, comprise nearly 20% of the entries.

Readerswill recognize that among the thousands of new ligand

systems that have been developed during the past few decades,

many may be organized into ‘‘superfamilies’’ of compounds

that are constituted from similar molecular platforms. An

attempt has been made to group these under a single, parent

compound, but this effort in some cases has been thwarted by

the historical, organic manner in which EROS has evolved, and

it has not always been possible to accomplish this ideal.

A list of recent review articles and monographs concerning

various aspects of cross-coupling reactions has been included,

which appears directly after this Introduction. These articles and

authoritative books detail both synthetic and mechanistic aspects

of these important transformations. The list is divided into several

sections. Thefirst includes articles and books on general aspects of

cross-coupling, broadly defined. The remainder of the reviews are

organized according to the specific type of cross-coupling reaction

involved, arranged by their now-familiar monikers. Subsequently,

the various catalyst components are listed in alphabetical order in

keeping with the EROS and eEROS format.

Because cross-coupling reactions play such an integral role in

virtually all aspects of modern synthetic organic chemistry, we

hope that this compilation will prove useful as a first reference

source to those seeking a comprehensive, authoritative single

volume for information on the catalyst components for various

cross-coupling protocols.

Gary A. MolanderDepartment of Chemistry

University of Pennsylvania

Philadelphia, PA, USA

Recent Review Articles and Monographs

General Cross-Coupling

Tsuji, J.PalladiumReagents andCatalysts;Wiley: Chichester,

1995.

Diederich, F.; Stang, P. J., Eds. Metal-Catalyzed Cross-

Coupling Reactions; Wiley-VCH: Weinheim, 1998.

Riermeier, T. H.; Zapf, A.; Beller, M. Part 3: Palladium-

catalyzed reactions for fine chemical synthesis. Palladium-

catalyzed C–C– and C–N–coupling reactions of aryl chlorides,

Top. Catal. 1998, 4, 301.Genet, J.-P.; Savignac, M. Recent developments of palladium(0)

catalyzed reactions in aqueous medium, J. Organomet. Chem. 1999,576, 305.

Amatore, C.; Jutand, A. Anionic Pd(0) and Pd(II) intermedi-

ates in palladium-catalyzed Heck and cross-coupling reactions,

Acc. Chem. Res. 2000, 33, 314.Frost, C. G. Palladium catalyzed coupling reactions. In Rodd’s

Chemistry of Carbon Compounds, 2nd Edition; Sainsbury, M.,

Ed.; Elsevier: Amsterdam, 2001, pp 315–350.

Miyaura, N., Ed. Cross-Coupling Reactions, A Practical

Guide; Springer-Verlag: Berlin, 2002.

Negishi, E., Ed.Handbook of Organopalladium Chemistry for

Organic Synthesis; Wiley: New York, 2002.

Cardenas, D. J. Advances in functional-group-tolerant metal-

catalyzed alkyl–alkyl cross–coupling reactions, Angew. Chem.,

Int. Ed. 2003, 42, 384.Bedford, R. B. Palladacyclic catalysts in C–C and C–

heteroatombond-forming reactions,Chem. Commun. 2003, 1787.De Maier, A.; Diederich, F., Eds. Metal-Catalyzed Cross-

Coupling Reactions, 2nd Edition; Wiley-VCH: Weinheim,

2004.

Shibasaki, M.; Vogl, E. M.; Ohshima, T. Heck reaction,

Comprehensive Asymmetric Catal., Suppl. 2004, 1, 73.Jutand, A. Dual role of nucleophiles in palladium-catalyzed

Heck, Stille, and Sonogashira reactions, Pure Appl. Chem. 2004,76, 565.

Miyaura, N. Heck and cross-coupling reactions: two core

chemistries in metal-catalyzed organic syntheses, Adv. Synth.

Catal. 2004, 346, 1522.Farina, V. High-turnover palladium catalysts in cross-coupling

and Heck chemistry: a critical overview, Adv. Synth. Catal. 2004,346, 1553.

Tsuji, J., Ed. Topics in Organometallic Chemistry: Palladium

in Organic Synthesis; Springer-Verlag: Berlin, 2005.

Nicolaou, K. C.; Bulger, P. G.; Sarlah, D. Palladium-catalyzed

cross-coupling reactions in total synthesis,Angew. Chem., Int. Ed.

2005, 44, 4442.

Christmann, U.; Vilar, R. Monoligated palladium species as

catalysts in cross-coupling reactions, Angew. Chem., Int. Ed.

2005, 44, 366.Nilsson, P.; Olofsson, K.; Larhed, M. Microwave-assisted and

metal-catalyzed coupling reactions, Top. Curr. Chem. 2006, 266, 103.Kantchev, E. A. B.; O’Brien, C. J.; Organ, M. G. Pd-N-

heterocyclic carbene (NHC) catalysts for cross-coupling reac-

tions, Aldrichim. Acta 2006, 39, 97.Roglans, A.; Pla-Quintana, A.;Moreno-Manas,M.Diazonium

salts as substrates in palladium-catalyzed cross-coupling reac-

tions, Chem. Rev. 2006, 106, 4622.Mauger, C. C.; Mignani, G. A. Synthetic applications of

Buchwald’s phosphines in palladium-catalyzed aromatic-bond-

forming reactions, Aldrichim. Acta 2006, 39, 17.Phan, W. T. S.; Van Der Slugs, M.; Jones, C. W. On the nature

of the active species in palladium catalyzed Mizoroki–Heck

and Suzuki–Miyaura couplings-homogeneous or heterogeneous

catalysis, a critical review, Adv. Synth. Catal. 2006, 348, 609.Clavier, H.; Nolan, S. P.N-Heterocyclic carbenes. Advances in

transition metal-mediated transformations and organocatalysis,

Annu. Rep. Prog. Chem., Sect. B: Org. Chem. 2007, 103, 193.Yin, L.; Liebscher, J. Carbon–carbon coupling reactions catalyzed

by heterogeneous palladium catalysts, Chem. Rev. 2007, 107, 133.

Mizoroki–Heck Coupling

Herrmann, W. A. Catalytic carbon–carbon coupling by

palladium complexes: Heck reactions. In Applied Homogeneous

Catalysis with Organometallic Compounds; Cornils, B.; Herrmann,

W. A., Eds.; VCH: Weinheim, 1996, Vol. 2, pp 712–732.

Gibson, S. E.; Middleton, R. J. The intramolecular Heck

reaction, Contemporary Org. Synth. 1996, 3, 447.Shibasaki, M.; Boden, C. D. J.; Kojima, A. The asymmetric

Heck reaction, Tetrahedron 1997, 53, 7371.Crisp, G. T. Variations on a theme: recent developments on the

mechanism of the Heck reaction and their implications for

synthesis, Chem. Soc. Rev. 1998, 27, 427.Guiry, P. J.; Hennessy, A. J.; Cahill, J. P. The asymmetric Heck

reaction: recent developments and applications of new palladium

diphenylphosphinopyrrolidine complexes, Top. Catal. 1998, 4, 311.Beller, M.; Riermeier, T. H.; Stark, G. Palladium-catalyzed

olefinations of aryl halides (Heck reaction) and related transforma-

tions. In Transition Metals for Organic Synthesis; Beller, M.; Bolm,

C., Eds.; Wiley-VCH Verlag: Weinheim, 1998, Vol. 1, pp 208–240.

Shibasaki, M.; Vogl, E. M. Heck reaction. In Comprehensive

Asymmetric Catalysis; Jacobsen, E. N.; Pfaltz, A.; Yamamoto, H.,

Eds.; Springer-Verlag: Berlin, 1999, Vol. 1, pp 457–487.

RECENT REVIEW ARTICLES AND MONOGRAPHS 1

Avoid Skin Contact with All Reagents

Shibasaki, M.; Vogl, E. M. The palladium-catalyzed arylation

and vinylation of alkenes-enantioselective fashion, J. Organomet.

Chem. 1999, 576, 1.Loiseleur, O.; Hayashi, M.; Keenan, M.; Schmees, N.; Pfaltz,

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Whitcombe, N. J.; Hii, K. K.; Gibson, S. E. Advances in the

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Dounay,A. B.;Overman, L. E. The asymmetric intramolecular

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Tetrahedron 2005, 61, 11771.Koehler, K.; Proeckl, S. S.; Kleist, W. Supported palladium

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Heck coupling reactions, Tetrahedron 2007, 63, 6949.Knowles, J. P.; Whiting, A. The Heck–Mizoroki cross-

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2007, 5, 31.Weck, M.; Jones, C. W. Mizoroki–Heck coupling using

immobilizedmolecular precatalysts: leaching active species from

Pd pincers, entrapped Pd salts, and Pd NHC complexes, Inorg.

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Suzuki–Miyaura Cross-Coupling

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Suzuki, A. Recent advances in the cross-coupling reactions of

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Chemler, S. R.; Trauner, D.; Danishefsky, S. J. The B-alkyl

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Kotha, S.; Lahiri, K.; Kashinath, D. Recent applications of the

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Molander, G. A.; Figueroa, R. Organotrifluoroborates:

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Negishi Cross-Coupling

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Palladium- or nickel-catalyzed cross-coupling with organometals

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2 RECENT REVIEW ARTICLES AND MONOGRAPHS

A list of General Abbreviations appears on the front Endpapers

Kumada–Tamao, Corriu Cross-Coupling

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Sonogashira Cross-Coupling

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Tsuji–Trost Reaction

Trost, B. M. New rules of selectivity: allylic alkylations

catalyzed by palladium, Acc. Chem. Res. 1980, 13, 385.Trost, B. M. Designing a receptor for molecular recognition in

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Palladium-catalyzed allylic alkylation. In Green Chemistry;

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Oxford, UK, 1998, pp 101–110.

Trost, B. M.; Lee, C. Asymmetric allylic alkylation reactions

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decarboxylative additions of enolates, Eur. J. Org. Chem. 2005,1715.

Braun,M.;Meier, T. Tsuji–Trost allylic alkylation with ketone

enolates, Angew. Chem., Int. Ed. 2006, 45 6952.Trost, B. M.; Machacek, M. R.; Aponick, A. Predicting the

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palladium-catalyzed allylic alkylations of preformed enolates,

Synlett 2006, 661.Helmchen,G.Asymmetric allylic substitutions. InAsymmetric

Synthesis; Christmann, M.; Braese, S., Eds.; Wiley-VCH Verlag:

Weinheim, 2007, pp 95-99.

Buchwald–Hartwig Reaction

Beller, M. Palladium-catalyzed amination of aryl halides—

catalysts on new routes to known targets, Angew. Chem., Int. Ed.

Engl. 1995, 34, 1316.Hartwig, J. F. Palladium-catalyzed amination of aryl halides.

Mechanism and rational catalyst design, Synlett 1997, 329.Baranano, D.; Mann, G.; Hartwig, J. F. Nickel and palladium-

catalyzed cross-couplings that form carbon–heteroatom and

carbon–element bonds, Curr. Org. Chem. 1997, 1, 287.Wolfe, J. P.; Wagaw, S.; Marcoux, J.-F.; Buchwald, S. L.

Rational development of practical catalysts for aromatic carbon–

nitrogen bond formation, Acc. Chem. Res. 1998, 31, 805.Hartwig, J. F. Carbon–heteroatom bond-forming reductive

eliminations of amines, ethers, and sulfides, Acc. Chem. Res.

1998, 31, 852.

Hartwig, J. F. Transition metal catalyzed synthesis of

arylamines and aryl ethers from aryl halides and triflates: scope

and mechanism, Angew. Chem., Int. Ed. 1998, 37, 2046.Yang, B. H.; Buchwald, S. L. Palladium-catalyzed amination

of aryl halides and sulfonates, J. Organomet. Chem. 1999, 576,125.

Hartwig, J. F. Approaches to catalyst discovery. New carbon–

heteroatom and carbon–carbon bond formation,PureAppl. Chem.

1999, 71, 1417.Hartwig, J. F. Palladium-catalyzed amination of aryl halides

and sulfonates. In Modern Arene Chemistry; Astruc, D., Ed.;

Verlag: Weinheim, 2002, pp 107–168.

Hartwig, J. F. Palladium-catalyzed amination of aryl halides

and related reactions. In Handbook of Organopalladium Chem-

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Sons, Inc.: Hoboken, NJ, 2002, Vol. 1, pp 1051–1096.

Muci, A. R.; Buchwald, S. L. Practical palladium catalysts for

C–N and C–O bond formation, Top. Curr. Chem. 2002, 219,131.

Schlummer, B.; Scholz, U. Palladium-catalyzed C–N and C–

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Adv. Synth. Catal. 2004, 346, 1599.Jiang, L.; Buchwald, S. L. Palladium-catalyzed aromatic

carbon–nitrogen bond formation. In Metal-Catalyzed Cross-

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Hartwig, J. F. Discovery and understanding of transition-

metal-catalyzed aromatic substitution reactions, Synlett 2006,1283.

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Industrial-scale palladium-catalyzed coupling of aryl halides

and amines—a personal account,Adv. Synth. Catal. 2006, 348, 23.

4 RECENT REVIEW ARTICLES AND MONOGRAPHS


1-ADAMANTYL-DI-tert-BUTYLPHOSPHINE 5

A1-Adamantyl-di-tert-butylphosphine

P

[338799-92-1] C18H33P (MW 280.83)

(ligand used for palladium-catalyzed cross-coupling reactions)

Physical Data: not reported.Solubility: soluble in ether, benzene, toluene, THF.Form Supplied in: white solid.Analysis of Reagent Purity: 31P NMR (C6D6): δ 63.0.Preparative Methods: prepared from the cuprate-mediated addi-

tion of 1-adamantyl Grignard reagent to But2PCl.

Purification: distillation at 159–165 ◦C at 1 Torr under nitrogenatmosphere.

Handling, Storage, and Precautions: it is prone to oxidation inair and should be kept under inert atmosphere.

Overview. 1-Adamantyl di-tert-butylphosphine is a slightlymore hindered variant of tri-tert-butylphosphine that emergedfrom the synthesis of a library of phosphines, work on catalyticcoupling, and work on synthesis of organometallic intermediatesin cross-coupling processes. Certain coupling processes have oc-curred in higher yields or under milder conditions with this lig-and than with t-Bu3P. In addition, some palladium catalyst pre-cursors containing this ligand are significantly more stable to airand moisture than those containing t-Bu3P, and arylpalladium(II)halide complexes of this ligand are more thermally stable thanthose containing t-Bu3P.

Ligand Synthesis. 1-Adamantyl di-tert-butylphosphine isprepared from the cuprate-mediated addition of 1-adamantyl Grig-nard reagent to But

2PCl as shown in eq 1.1

MgBrtBu2PCl

Et2O PtBu2

CuI, LiBr+

85%

(1)

Preparation of 1-AdMgBr from 1-bromoadamantane is some-what challenging on large scale because of competing radical cou-pling of the adamantyl groups2–4 and is best conducted withoutstirring.4,5 1-Adamantyl di-tert-butylphosphine was first preparedas part of a library of sterically hindered monophosphines testedusing a qualitative fluorescence assay for room-temperature Heckreactions of bromoarenes1 (eq 2) and later a fluorescence reso-

nance energy transfer system for the coupling of aryl halides withcyanoesters (eq 3).6

ArBr RR

Ar+

2.5% Pd(dba)2

5.0% (1-Ad)PtBu2

88–99%

1.2 equiv NEt3DMF, rt

(2)

NN

BocN

Br

NMe2

O2SN

O

O

CN

O2SN

NMe2

O

O

CNBocN

NN

+

Strong fluorescence

catalyst

Weak fluorescence

(3)

Catalysis with Palladium Complexes of 1-Adamantyl-di-tert-butylphosphine. The combination of adamantyl di-tert-butylphosphine and a palladium precursor typically reacts withsimilar rates and yields to those of tri-tert-butylphosphine.6–8

However, the precatalyst with the general formula (LPdBr)2 wasmore active when L = 1-adamantyl di-tert-butylphosphine thanwhen L = P(t-Bu)3.9 Table 1 provides a series of aminations of arylhalides using the dimeric Pd(I) species containing t-Bu3P and 1-adamantyl di-tert-butylphosphine as ligand. On the practical side,the dinuclear complex {[(1-Ad)P(t-Bu)2]PdBr}2was stable to airindefinitely as a solid, whereas [(t-Bu)3PPdBr]2can be weighedin air, but should be stored under nitrogen.

Organometallic Complexes of 1-Adamantyl-di-tert-butyl-phosphine. Differences in the stability of palladium com-plexes of 1-adamantyl di-tert-butylphosphine and tri-tert-butylphosphine were observed when conducting the synthesisof arylpalladium(II) complexes. As shown in eqs 4 and 5, theunusual three-coordinate arylpalladium halide complexes ligatedby 1-adamantyl di-tert-butylphosphine are formed in good yield,whereas the analogous reaction with Pd(Pt-Bu3)2 occurs in yieldsless than 50%. In addition, the arylpalladium halide complexesligated by 1-adamantyl di-tert-butylphosphine complex are morethermally stable and crystallize more readily, due to stabilizationby an agostic interaction of a methylene hydrogen with the Pd(II)center.10,11


6 1-ADAMANTYL-DI-tert-BUTYLPHOSPHINE

1-AdtBu2P Pd Br

PhPd[1-AdPtBu2]2

PhBr

81%

(4)neat

70 °C

Table 1 Amination of aryl halides with {[(1-Ad)P(t-Bu)2]PdBr}2 ascatalysta

Me

ClHN O

Cl

Me

MeO

Cl

O2N

Cl

tBuCO2

Cl

t-Bu

Br

t-Bu

Br

t-Bu

Br

t-Bu

Br

HN O

Me N O

N O

Me

MeO

NBu2

O2N

NBu2

tBuCO2

NBu2

t-Bu

NBu2

t-Bu

NMePh

t-Bu

NPh2

t-Bu

NHPh

HNBu2

HNBu2

HNBu2

HNBu2

HNMePh

HNPh2

H2NPh

Aryl halideEntry

3

4

5

6

7

8

9

Amine Product Yieldb

87%

97%

>99%

96%

98%

96%

1

2

88%

68%

82%

aReaction were conducted on 1 mmol scale in THF (1 mL) at room temper-

ature for 15 min or 1 h (entry 8). The relative amounts of arly halide, amine,

NaOt-Bu, and [(R3P)PdBr]2 was 200:210:300:1.bYields of isolated products are an average of two runs.

1-AdtBu2P Pd I

Ph

PhI

87%

neat70 °C

Pd[1-AdPtBu2]2 (5)

1. Stambuli, J. P.; Stauffer, S. R.; Shaughnessy, K. H.; Hartwig, J. F., J. Am.Chem. Soc. 2001, 123, 2677.

2. Dubois, J. E.; Bauer, P.; Molle, G.; Daza, J., C. R. Hebd. Seances Acad.Sci., Ser. C 1977, 284, 145.

3. Molle, G.; Bauer, P.; Dubois, J. E., J. Org. Chem. 1982, 47, 4120.

4. Yurchenko, A. G.; Fedorenko, T. V.; Rodionov, V. N., Zh. Org. Khim.1985, 21, 1673.

5. Molle, G.; Bauer, P.; Dubois, J. E., J. Org. Chem. 1982, 47, 4120.

6. Stauffer, S. R.; Beare, N.; Stambuli, J. P.; Hartwig, J. F., J. Am. Chem.Soc. 2001, 123, 4641.

7. Wu, L. Y.; Hartwig, J. F., J. Am. Chem. Soc. 2005, 127, 15824.

8. Beare, N. A.; Hartwig, J. F., J. Org. Chem. 2002, 67, 541.

9. Stambuli, J. P.; Kuwano, R.; Hartwig, J. F., Angew. Chem., Int. Ed. Engl.2002, 41, 4746.

10. Stambuli, J. P.; Bühl, M.; Hartwig, J. F., J. Am. Chem. Soc. 2002, 124,9346.

11. Stambuli, J. P.; Incarvito, C. D.; Buhl, M.; Hartwig, J. F., J. Am. Chem.Soc. 2004, 126, 1184.

John F. Hartwig & Giang VoUniversity of Illinois, Urbana, IL, USA


BENZYLCHLOROBIS(TRIPHENYLPHOSPHINE)PALLADIUM(II) 7

BBenzylchlorobis(triphenylphosphine)-palladium(II)1

PdPh3P

Ph3P

ClPh

(1)

[22784-59-4] C43H37ClP2Pd (MW 757.59)

(catalyst for the cross coupling1 of alkyl-, vinyl-, alkynyl-, andallylstannane groups with acyl chlorides,2 allyl halides,3 vinyl

triflates, and iodides4)

Physical Data: mp 166–170 ◦C.Solubility: sol THF, benzene, and other organic solvents.Form Supplied in: crystalline; commercially available.Preparative Methods: may be prepared from benzyl chloride and

(Ph3P)4Pd in benzene at room temperature, washed with Et2O,and dried under vacuum.5

Handling, Storage, and Precautions: is an air-stable solid andremains stable in solution. Irritant.

Cross Coupling Reactions with Organostannane Com-pounds. Palladium catalysis of cross coupling reactions is wellestablished in organic chemistry.1 Benzylchlorobis(triphenyl-phosphine)palladium(II) (1), first reported in 1969,2 is used ex-tensively for these reactions. Other palladium complexes, suchas dichlorobis(triphenylphosphine)palladium(II) and tetrakis-(triphenylphosphine)palladium(0), catalyze cross coupling reac-tions; however, the title compound generally provides higheryields in shorter reaction times. Most common is the couplingof an organotin compound with an acyl halide to produce ke-tone products (eq 1), which has many advantages over existingmethods of preparing ketones from acyl chlorides. The yields arehigh, and in many cases, nearly quantitative. Both the organotincompound and the catalyst are air stable. The reaction tolerates awide variety of functional groups; ester, alkene, nitro, nitrile, halo,methoxy, silyloxy, vinyl ether, and even aldehyde remain intactduring the reaction. Sterically hindered acid chlorides will react,and conjugate addition with �,�-unsaturated acid chlorides doesnot occur. Further, if a vinyl-, aryl-, or alkynyl-trialkylstannane is

+R2

4Sn+ (1)

THF or HMPA, 65 °C1 min – hoursR3

3SnR2or

R1 = alkyl, aryl, vinyl, alkynyl, allyl, -OR, -NR2R2 = alkyl, aryl, vinyl, alkynyl, allylR3 = Bu, Me

or

R33SnCl

R23SnCl

R1 Cl

O O

R1 R2

(1) (0.1–5 mol %)

used, only the vinyl, aryl, or alkynyl group is transferred. Withstannanes as substituents on a stereogenic center, the reaction stan-nanes as substituents on a stereogenic center, the reaction proceedswith stereochemical inversion of the stereogenic center.6 Acyl-stannanes can be prepared by the coupling of acyl halides anddistannyl species.7

Aldehydes can be prepared from acid chlorides andtri-n-butyltin hydride in the presence of (1).8 While thisreduction can be performed by mixing the substrate and Bu3SnH,ester byproducts and other products resulting from radicalreactions occur without the palladium catalyst. 1,2-Diketones canbe made easily by the reaction of a 1-methoxyvinylstannane andan acid chloride, followed by hydrolysis (eq 2).9 A similar 2-methoxyvinylstannane was employed in the synthesis of agglom-erin A and (±)-carolinic acid.10 Vinylstannanes and acyl chlorideshave been coupled intramolecularly to provide 11-, 12-, 14-, 16-,and 20-membered macrocycles in 32–72% yields.11

SnMe3

OMe

RCOCl

R

O

OMeH3O+

R

O

O

Me

R = alkyl, aryl

(2)

C6H6

reflux 1 h73–86%

+(1) (1 mol %)

Allylic halides can be coupled with organostannanes withoutallylic transposition.3b The reaction takes place with inversion ofstereochemistry at the allylic carbon, and double bond geometryremains intact for acyclic substrates (eq 3).3c In addition, car-bon monoxide can be inserted during the course of the reactionto provide ketone products.3a,12 Vinyl iodides couple in a simi-lar fashion,4a and the coupling of vinyl triflates was used in thesynthesis of pleraplysillin.4b

Cl

CO2Me

CO atmosphereTHF, 40 °C

Bu3SnR

R

CO2Me

COR

CO2Me(3)

THF, 40 °C

R = Ph, CH=CH2

+

(1) (0.5 mol %)

(1) (0.5 mol %)

Ether Cleavage and Formation Reactions. While the crosscoupling reactions of organotin compounds in the presence of(1) tolerate a great deal of functionality, cyclic (5-membered orless), allylic and benzylic ethers can be cleaved upon reaction withan acid chloride catalyzed by the presence of trialkyltin chloride(eq 4).13 Aliphatic and phenolic ethers are not consumed. Com-plementary to this method of ether substrate cleavage, epoxides,oxetanes, and tetrahydrofurans can be formed by the reaction ofbromo ketones and allylic stannanes or �-ketostannanes (eq 5).14

Other alkylstannanes fail to give cyclic ethers.

+

(1) (0.4 mol %)Bu3SnCl (15 mol %)

(4)O

O OCl

Cl

O

THF, 63 °C, 48 h 85%


8 [1,1′-BIPHENYL]-2-YLDICYCLOHEXYLPHOSPHINE

( )n

n = 0, 1, 2

BumSnR34-m +

( )n THF, 63 °C, 3–48 h

55–90% (5)R1 R2

O Br OR2R1

R3

(1) (2.5 mol %)

1. For reviews on metal catalyzed cross coupling reactions see: (a) Stille,J. K., Angew. Chem., Int. Ed. Engl. 1986, 25, 508. (b) Stille, J. K., PureAppl. Chem. 1985, 57, 1771. (c) Negishi, E.-I., Acc. Chem. Res. 1982,15, 340.

2. (a) Milstein, D.; Stille, J. K., J. Am. Chem. Soc. 1978, 100, 3636. (b)Milstein, D.; Stille, J. K., J. Org. Chem. 1979, 44, 1613. (c) Logue, M.W.; Teng, K., J. Org. Chem. 1982, 47, 2549. (d) Labadie, J. W.; Tueting,D.; Stille, J. K., J. Org. Chem. 1983, 48, 4634. (e) Verlhac, J.-B.; Pereyre,M., Tetrahedron 1990, 46, 6399. (f) Blanchot, V.; Fétizon, M.; Hanna, I.,Synthesis 1990, 755. (g) Kang, K.-T.; Kim, S. S.; Lee, J. C., TetrahedronLett. 1991, 32, 4341. (h) Degl’Innocenti, A.; Dembech, P.; Mordini, A.;Ricci, A.; Seconi, G., Synthesis 1991, 267. (i) Balas, L.; Jousseaume, B.;Shin, H.; Verlhac, J.-B.; Wallian, F., Organometallics 1991, 10, 366.

3. (a) Milstein, D.; Stille, J. K., J. Am. Chem. Soc. 1979, 101, 4992. (b)Godschalx, J.; Stille, J. K., Tetrahedron Lett. 1980, 21, 2599. (c) Sheffy,F. K.; Stille, J. K., J. Am. Chem. Soc. 1983, 105, 7173. (d) Liebeskind,L. S.; Wang, J., Tetrahedron 1993, 49, 5461.

4. (a) Stille, J. K.; Groh, B. L., J. Am. Chem. Soc. 1987, 109, 813. (b) Scott,W. J.; Stille, J. K., J. Am. Chem. Soc. 1986, 108, 3033. (c) Hinkle, R. J.;Poulter, G. T.; Stang, P. J., J. Am. Chem. Soc. 1993, 115, 11626.

5. (a) Fitton, P.; McKeon, J. E.; Ream, B. C., J. Chem. Soc. (C) 1969, 370.(b) Lau, K. S. Y.; Wong, P. K.; Stille, J. K., J. Am. Chem. Soc. 1976, 98,5832. (c) Lau, K. S. Y.; Stille, J. K., J. Am. Chem. Soc. 1976, 98, 5841.

6. Labadie, J. W.; Stille, J. K., J. Am. Chem. Soc. 1983, 105, 669.

7. Mitchell, T. N.; Kwetkat, K., Synthesis 1990, 1001.

8. Four, P.; Guibe, F., J. Org. Chem. 1981, 46, 4439.

9. Soderquist, J. A.; Leong, W. W.-H., Tetrahedron Lett. 1983, 24, 2361.

10. Ley, S. V.; Trudell, M. L.; Wadsworth, D. J., Tetrahedron 1991, 47, 8285.

11. Baldwin, J. E.; Adlington, R. M.; Ramcharitar, S. H., J. Chem. Soc.,Chem. Commun. 1991, 940.

12. Liebeskind, L. S.; Yu, M. S.; Fengl, R. W., J. Org. Chem. 1993, 58, 3543.

13. Pri-Bar, I.; Stille, J. K., J. Org. Chem. 1982, 47, 1215.

14. Pri-Bar, I.; Pearlman, P. S.; Stille, J. K., J. Org. Chem. 1983, 48, 4629.

Gregory R. Cook & John R. StilleMichigan State University, East Lansing, MI, USA

[1,1′′′-Biphenyl]-2-yldicyclohexylphosphine

PCy2

[247940-06-3] C24H31P (MW 350.48)

(reagent used as a ligand for a variety of palladium-catalyzedreactions)

Alternate Name: 2-(dicyclohexylphosphino)biphenyl.Physical Data: mp 103 ◦C.Solubility: soluble in most organic solvents.Form Supplied in: white crystalline solid.

Purification: recrystallized from hot methanol.Handling, Storage, and Precautions: stable to air and moisture.

Introduction. 2-(Dicyclohexylphosphino)biphenyl) (1) is amonodentate phosphine ligand that is prepared via lithiation of2-bromobiphenyl followed by phosphinylation with dicyclohexyl-chlorophosphine.1 Ligand 1 was developed by Buchwald and firstdescribed in 1999 for use in Pd-catalyzed Suzuki–Miyaura coup-lings and N-arylation reactions of aryl bromides and chlorides.The high activity of catalysts supported by ligand 1 is believedto be due to a combination of steric and electronic properties.The ligand is electron rich, which facilitates oxidative additionof aryl halides to Pd(0), and is sterically bulky, which promotescarbon–carbon and carbon–heteroatom bond-forming reductiveelimination. Unlike many electron-rich phosphines, 1 is air-stableat room temperature in crystalline form and in solution.2 Ligand1 has been used extensively in various palladium-catalyzed cross-coupling reactions,3 which are described in this article.

Suzuki–Miyaura Couplings. The palladium-catalyzed crosscoupling of organoboron reagents with aryl/alkenyl halides(Suzuki coupling) is one of the most common methods used for theformation of Csp2–Csp2 bonds.4–7 Ligand 1 has been frequentlyemployed in these transformations.

The high activity of catalysts supported by 1 allows Suzukicoupling reactions to be conducted with relatively low catalystloadings. For example, the coupling of 4-bromo-tert-butylbenzene with phenylboronic acid was achieved using only0.001 mol % palladium (eq 1).1,8 The Suzuki coupling of un-activated aryl chlorides can also be effected, although slightlyhigher catalyst loadings are typically required (0.05–1 mol %Pd).1,8 High turnover numbers have also been obtained using apalladium(0) monophosphine complex composed of diallyl etherand 1.9

Br

t-Bu

B(OH)2

Ph

t-Bu

+

0.001% Pd(OAc)2

0.002% 1

(1)

92%

K3PO4

toluene, 100 °C

The Pd(OAc)2/1 catalyst system has also been employed forthe Suzuki coupling of sensitive substrates. For example, the crosscoupling of unstable 1-azulenyl triflate 2 with triethylborane wasachieved using this catalyst (eq 2). The product of this transfor-mation (3) is a key intermediate in Danheiser’s synthesis of theantiulcer drug egualen sodium (KT1-32).10,11 This catalystoperates efficiently under sufficiently mild conditions such thata broad array of functional groups are tolerated.12–15

Catalysts supported by 1 are often used for cross-couplingreactions of heteroaryl halides. In a representative example,C-6 arylpurine 2′-deoxyriboside analog 5 was prepared from thecorresponding C-6 bromopurine substrate 4 (eq 3).16 A similarstrategy allowed the construction of C-6 aryl 2′-deoxyguanosinederivatives from the corresponding O6-aryl sulfonates.17 A broad


[1,1′-BIPHENYL]-2-YLDICYCLOHEXYLPHOSPHINE 9

array of heterocycles can be generated using this chemistry, in-cluding arylpyridines, arylquinolines,18 and C-4 aryl coumarins.19

Resin-bound chlorotriazines have also been used as couplingpartners in these transformations.20

i-Pr

Br

O

N2

Et

i-Pr

OTf

i-Pr

(2)

42% over two steps

1. 1% Rh2(OPiv)4

5% Pd(OAc)2

7.5% 1

2

3

2. PhNTf2, DMAP

Et3B, KFTHF, 65 °C

N

Br

N

NN

O

OTBDMS

TBDMSO

N

NN

N

Ph

O

OTBDMS

TBDMSO

10% Pd(OAc)2

15% 1PhB(OH)2

(3)

91%5

4

K3PO4

dioxane, 100 °C

Although most Suzuki coupling reactions use boronic acids asthe nucleophilic coupling partner, these reagents can be difficultto purify, and the boronic acid moiety is usually too sensitive totolerate multistep sequences of reactions. In contrast aryl, alkyl,and alkenyl potassium trifluoroborates have much better physicaland chemical properties and are finding many applications in Pd-catalyzed cross-coupling reactions.21 These reagents can be pre-pared in highly pure form through recrystallization, and the triflu-oroborate moiety is tolerant of conditions used in many commonorganic transformations. As shown below (eq 4), the Pd(OAc)2/1catalyst system provides good results in Suzuki coupling reactionsof cyclopropyl potassium trifluoroborates with aryl bromides.22

However, in many cross-coupling reactions of organotrifluorobo-rate reagents, superior results are obtained with other ligands.21

Although 1 provides excellent results in a number of Pd-catalyzed Suzuki coupling reactions, related biaryl(dialkyl)-phosphine derivatives bearing substituents at the 2′- and6′-positions often show higher reactivity and are effective witha broader array of substrates.23–25 These ligands have foundapplications in transformations that were not efficiently catalyzedby Pd/1.

Ac

BrBF3K

OH OBnH

OH

OBn

H

Ac

+

3% Pd(OAc)2

6% 1

K3PO4, toluene, H2O100 °C

(4)

89%

Other Pd-catalyzed Cross-coupling Reactions. In additionto the Suzuki coupling reactions described above, Pd/1 catalystshave been used in several other Pd-catalyzed cross-coupling reac-tions of aryl halides with main-group organometallic reagents. Forexample, a catalyst composed of Pd(OAc)2/1 was shown to beoptimal in Negishi coupling26,27 reactions of aryl triflates witharylzinc phenoxides that afford biaryl phenols (eq 5).28 Thismethod can be employed for the synthesis of oligoarene productsvia an iterative sequence of cross coupling followed by triflationof the resulting phenol product.

N

OTf

OLiClZn

N

OH

+

1% Pd(OAc)2

1.2% 1

(5)

76%

THF, 60 °C

Several examples of Pd2(dba)3/1-catalyzed Hiyama couplingreactions of organosilicon reagents with aryl, alkenyl, or alkynylhalides have been reported.29 As shown below (eq 6), this catalystprovided excellent results in couplings of phenyltrimethoxysilanewith aryl halides30 and triflates.31

Cl

MeO

Ph

MeOPhSi(OMe)3

10% Pd2(dba)3

15% 1(6)

71%

+TBAF

DMF, 85 °C

The methylation of aryl and vinyl halides with an air stableDABCO adduct of trimethylaluminum was achieved using a Pd/1catalyst.32 As shown in eq 7, the methylation of 4-bromobenzo-nitrile with (AlMe3)2(DABCO) provided 4-cyanotoluene in 92%yield. These conditions are sufficiently mild that substrates bear-ing nitriles, hydroxyl groups, esters, aldehydes, and nitro groupsare efficiently transformed without degradation of the functionalgroup.

A few examples of the use of ligand 1 in Pd-catalyzed�-arylation of ketones have been described. For example, thecoupling of cycloheptanone with aryl bromide 6 proceeded in80% yield with the Pd(OAc)2/1 catalyst system (eq 8),33 andligand 1 was also optimal for Pd-catalyzed �-arylations of ethyl


10 [1,1′-BIPHENYL]-2-YLDICYCLOHEXYLPHOSPHINE

N-diphenylmethylideneglycinate with iodopurines under mildlybasic conditions (K3PO4).34 However, other biaryl-derived phos-phine ligands typically provide superior results in the majority ofPd-catalyzed ketone �-arylation reactions.33

Br

NC N

N

AlMe3

AlMe3

Me

NC

1.5% Pd2(dba)3

3% 1

92%

(7)+THF, 65 °C

Br

O

O

O

O

O

O

+

0.1% Pd(OAc)2

0.2% 1

80%

(8)

2 equiv 6

NaO–t-Butoluene, 45 °C

The C-2 arylation of pyrrole anions with aryl bromides can beaccomplished under relatively mild conditions with the use of aPd/1 catalyst and stoichiometric amounts of zinc chloride (eq 9).35

Ligand 1 was also shown to facilitate regioselective phenyla-tion of 4-oxazolecarboxylate with iodobenzene in the presenceof Cs2CO3.36

NaN

ZnCl2

Br

F3C CF3

HN

F3C

F3C

0.5% Pd(OAc)2

1% 1

(9)

90%

+ +THF, 80 °C

A single example of use of ligand 1 in a stereoselectivepalladium-catalyzed tandem Heck arylation/carbonylation reac-tion has been reported in the total synthesis of perophoramidine.As shown in eq 10, 7 was converted to 8 in 71% yield as a singlediastereomer.37

Palladium-catalyzed Carbon–Heteroatom Bond Forma-tion. The palladium-catalyzed amination of aryl halides is apowerful method for the synthesis of substituted or functionalizedarylamines,38,39 which are of particular importance in the pharma-ceutical industry.40,41 Ligand 1 is highly effective for palladium-catalyzed N-arylation reactions of aryl bromides,42 chlorides,42

and iodides (eq 11).43 Other related biaryl(dialkylphosphine)ligands also provide excellent results in these transformations,and ligands bearing substituents at the 2′ and 6-positions arefrequently more active than 1.42,44 The catalytic activity of 1diminishes as reactions progress, which results from the formationof catalytically inactive palladacycles via competing intramolecu-lar C–H activation of a 2′-aromatic hydrogen atom on the proximal

ring.45,46 In contrast, biaryl bearing substituents that block thesepositions do not undergo this side reaction and are more effectiveat low catalyst loadings.46

N

OI

BnO

OTBS

OPMP

NO

BnO OTBSCO2MeH

OPMP

10% Pd(OAc)2

30% 1

71%

(10)

8

7

NaOAc, CODMA, MeOH

85 °C

Cl

MeO2C

HN O+

N

O

MeO2C

1% Pd(OAc)2

2% 1

(11)

90%

K3PO4

DME, 80 °C

Ligand 1 has been employed in a variety of other Pd-catalyzedN-arylation or N-alkenylation reactions of aliphatic or aromaticamines. For example, use of 1 allows selective monoarylation ofdichloropyridines with aniline derivatives,47 and has been used inN-arylation reactions of bromoporphyrin derivatives.48 Primaryanilines can be easily obtained from reactions of aryl halides withammonia equivalents (LiHMDS or Ph3SiNH2),49,50 and enamineshave been prepared via Pd/1-catalyzed reactions of vinyl triflateswith secondary amines.51 The Pd/1 catalyst system has also beenused in microwave-promoted coupling reactions of azaheteroarylchlorides with various amines.52,53

Although a number of different phosphine ligands are suitablefor Pd-catalyzed N-arylation reactions involving aliphatic or aro-matic amine substrates,38–41 the N-arylation of heterocycles ismuch more difficult, and relatively few palladium catalysts effec-tively promote this transformation.54 As shown below, ligand 1 isa useful ligand for the N-arylation of indoles.55 For example, arylbromide 6 was coupled with 2-methylindole to afford N-aryl in-dole product 9 in 67% yield (eq 12). Despite the utility of 1 in thesetransformations, the Pd-catalyzed N-arylation of heterocyclesremains challenging. However, highly effective copper catalystshave been developed for heterocycle N-arylation reactions thatfunction well with a broad array of substrate combinations.56,57

Palladium-catalyzed aryl carbon–boron bond forming reactionsare useful methods for the synthesis of organoboron reagents un-der mild conditions. The selective borylation of aryl bromides inthe presence of a primary amine functionality has been achievedusing a catalyst composed of Pd(OAc)2/1. As shown in eq 13,2-bromoaniline was coupled with pinacolborane to afford 10 in


[1,1′-BIPHENYL]-2-YLDICYCLOHEXYLPHOSPHINE 11

81% yield.58 Borylation of bromoindoles with pinacolborane waseffected using similar reaction conditions.59

Br

O O

NH

N

O

O

+

3% Pd(OAc)2

4.5% 1

(12)

67%9

6

NaO–t-Butoluene, 100 °C

Br

NH2

B

NH2

O

O

OB

OH

10

+

5% Pd(OAc)2

20% 1

(13)

81%

Et3N, dioxane80 °C

Tandem reactions or one-pot sequences of reactions involv-ing Pd-catalyzed N-arylation are useful ways to build complexand functionalized products rapidly. Ligand 1 is effective inseveral transformations of this type. For example, the tandemone-pot borylation/amination reaction of dichlorobenzene pro-vided a 19:1 mixture of borylated chloroaniline derivatives 11and 12 (eq 14).60 The Pd/1 catalyst has been employed in one-pot borylation/Suzuki coupling reactions of aryl halides,58 whichhave been utilized for the synthesis of biologically active biaryllactams,61 �-benzo[b]thienyldehydrophenylalanine derivatives,62

and the natural products hippadine and pratosine.63 Ligand 1has also been used in the synthesis of carbazole natural prod-uct murrastifoline-A via tandem intermolecular/intramolecular N-arylation of a 2,2′-dibromobiphenyl precursor.64,65

Cl

Cl

Cl BPin

Ph(H)N

Ph(H)N BPin

Cl

1. 2% (Ind)Ir(COD) 2% dmpe, HBPin

(14)

46%, 19:1

+

11

2. 1% Pd2(dba)3, 4% 1 PhNH2, K3PO4

DME, 100 °C

12

Enyne Cyclizations. Catalysts supported by ligand 1 haveshown utility in several cyclization/addition reactions of enynesubstrates. For example, silylstannation–cyclization of 1,6-enyne13 was effected by treatment with tributyl(trimethylsilyl)stan-nane and catalytic amounts of Pd2(dba)3 and ligand 1. This reac-tion provided a five-membered carbocyclic product (14) bearing

(tributylstannyl)methyl- and alkylidenesilane moieties in 71%yield (eq 15).66 A related enyne cyclization/addition reaction of15 was achieved using a Au(L)Cl/AgSbF6 catalyst (L = 1). Thistransformation occurs with net 1,7-addition of methanol to afford16 in 97% yield (eq 16).67,68 Under similar reaction conditions,alkyne substrates bearing aromatic substituents were transformedto tricyclic products. Ligand 1 also provides satisfactory results inPd-catalyzed cycloisomerization reactions of functionalized 1,6-dienes; although PCy3 or P(cyclopentyl)3 are more frequently em-ployed as ligands in these transformations.69

EtO2C

EtO2CSiMe3

SnBu3

EtO2C

EtO2C

1% Pd2(dba)3

4.8% 1

71%

(15)

1413

Me3SiSnBu3

toluene, 60 °C

EtO2C

EtO2C

EtO2C

EtO2C

OMe

2% AuLCl2% AgSbF6

97%

(16)

16

MeOH, rt

15

Oxidation. The oxidation of alcohols to ketones or aldehy-des under mild and environmentally sound conditions has beenachieved using catalytic amounts of Pd(dba)2 and ligand 1, withchlorobenzene serving as the stoichiometric oxidant.70,71 Forexample, alcohol 17 was converted to ketone 18 in 98% yieldunder these conditions (eq 17).

F F

OH

F F

O

1.5 equiv chlorobenzene1% Pd(dba)2, 3% 1

98%

(17)

17

18

K2CO3, toluene 105 °C

1. Wolfe, J. P.; Buchwald, S. L., Angew. Chem., Int. Ed. 1999, 38, 2413.

2. Barder, T. E.; Buchwald, S. L., J. Am. Chem. Soc. 2007, 129, 5096.

3. Frisch, A. C.; Zapf, A.; Briel, O.; Kayser, B.; Shaikh, N.; Beller, M.,J. Mol. Cat. A 2004, 214, 231.

4. Suzuki, A. In Metal-Catalyzed Cross-Coupling Reactions; Diederich, F.;Stang, P. J., Eds.; Wiley-VCH: Weinheim, 1998; p 49.

5. Suzuki, A. In Organopalladium Chemistry for Organic Synthesis,Negishi, E.-i., Ed.; Wiley-Interscience: New York, 2002; Vol. 1, p 249.

6. Miyaura, N., Top. Curr. Chem. 2002, 219, 11.

7. Bellina, F.; Carpita, A.; Rossi, R., Synthesis 2004, 2419.

8. Wolfe, J. P.; Singer, R. A.; Yang, B. H.; Buchwald, S. L., J. Am. Chem.Soc. 1999, 121, 9550.

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10. Kane, J. L., Jr.; Shea, K. M.; Crombie, A. L.; Danheiser, R. L., Org. Lett.2001, 3, 1081.


12 BIS(ACETONITRILE)[(1,2,5,6-η)-1,5-CYCLOOCTADIENE]-RHODIUM(1+),TETRAFLUOROBORATE(1-)

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12. Piatek, P.; Slomiany, N., Synlett 2006, 2027.

13. Tao, B.; Goel, S. C.; Singh, J.; Boykin, D. W., Synthesis 2002, 1043.

14. Kotharé, M. A.; Ohkanda, J.; Lockman, J. W.; Qian, Y.; Blaskovich, M.A.; Sebti, S. M.; Hamilton, A. D., Tetrahedron 2000, 56, 9833.

15. Ishikawa, S.; Manabe, K., Chem. Commun. 2006, 2589.

16. Lakshman, M. K.; Hilmer, J. H.; Martin, J. Q.; Keeler, J. C.; Dinh, Y. Q.V.; Ngassa, F. N.; Russon, L. M., J. Am. Chem. Soc. 2001, 123, 7779.

17. Lakshman, M. K.; Thomson, P. F.; Nuqui, M. A.; Hilmer, J. H.; Sevova,N.; Boggess, B., Org. Lett. 2002, 4, 1479.

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24. Anderson, K. W.; Buchwald, S. L., Angew. Chem., Int. Ed. 2005, 44,6173.

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33. Fox, J. M.; Huang, X.; Chieffi, A.; Buchwald, S. L., J. Am. Chem. Soc.2000, 122, 1360.

34. Hocek, M., Heterocycles 2004, 63, 1673.

35. Rieth, R. D.; Mankad, N. P.; Calimano, E.; Sadighi, J. P., Org. Lett. 2004,6, 3981.

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37. Seo, J. H.; Artman, G. D., III., Weinreb, S. M., J. Org. Chem. 2006, 71,8891.

38. Muci, A. R.; Buchwald, S. L., Top. Curr. Chem. 2002, 219, 131.

39. Hartwig, J. F. In Modern Arene Chemistry; Astruc, D., Ed.; Wiley-VCH:Weinheim, 2002; p 107.

40. Schlummer, B.; Scholz, U., Adv. Synth. Catal. 2004, 346, 1599.

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42. Wolfe, J. P.; Tomori, H.; Sadighi, J. P.; Yin, J.; Buchwald, S. L., J. Org.Chem. 2000, 65, 1158.

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44. Anderson, K. W.; Tundel, R. E.; Ikawa, T.; Altman, R. A.; Buchwald, S.L., Angew. Chem., Int. Ed. 2006, 45, 6523.

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46. Reid, S. M.; Boyle, R. C.; Mague, J. T.; Fink, M. J., J. Am. Chem. Soc.2003, 125, 7816.

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48. Gao, G. Y.; Chen, Y.; Zhang, X. P., J. Org. Chem. 2003, 68, 6215.

49. Huang, X.; Buchwald, S. L., Org. Lett. 2001, 3, 3417.

50. Lee, S.; Jorgensen, M.; Hartwig, J. F., Org. Lett. 2001, 3, 2729.

51. Willis, M. C.; Brace, G. N., Tetrahedron Lett. 2002, 43, 9085.

52. Maes, B. U. W.; Loones, K. T. J.; Lemière, G. L. F.; Dommisse, R. A.,Synlett 2003, 1822.

53. Loones, K. T. J.; Maes, B. U. W.; Rombouts, G.; Hostyn, S.; Diels, G.,Tetrahedron 2005, 61, 10338.

54. Mann, G.; Hartwig, J. F.; Driver, M. S.; Fernandez-Rivas, C., J. Am.Chem. Soc. 1998, 120, 827.

55. Old, D. W.; Harris, M. C.; Buchwald, S. L., Org. Lett. 2000, 2, 1403.

56. Antilla, J. C.; Klapars, A.; Buchwald, S. L., J. Am. Chem. Soc. 2002,124, 11684.

57. Klapars, A.; Antilla, J. C.; Huang, X.; Buchwald, S. L., J. Am. Chem.Soc. 2001, 123, 7727.

58. Baudoin, O.; Guénard, D.; Guéritte, F., J. Org. Chem. 2000, 65, 9268.

59. Stadlwieser, J. F.; Dambaur, M. E., Helv. Chim. Acta 2006, 89, 936.

60. Holmes, D.; Chotana, G. A.; Maleczka, R. E., Jr.; Smith, M. R., III, Org.Lett. 2006, 8, 1407.

61. Baudoin, O.; Cesario, M.; Guénard, D.; Guéritte, F., J. Org. Chem. 2002,67, 1199.

62. Abreu, A. S.; Ferreira, P. M. T.; Queiroz, M.-J. R. P.; Ferreira, I. C. F.R.; Calhelha, R. C.; Estevinho, L. M., Eur. J. Org. Chem. 2005, 2951.

63. Mentzel, U. V.; Tanner, D.; Tonder, J. E., J. Org. Chem. 2006, 71, 5807.

64. Kitawaki, T.; Hayashi, Y.; Ueno, A.; Chida, N., Tetrahedron 2006, 62,6792.

65. Kitawaki, T.; Hayashi, Y.; Chida, N., Heterocycles 2005, 65, 1561.

66. Lautens, M.; Mancuso, J., Synlett 2002, 394.

67. Nieto-Oberhuber, C.; Lopez, S.; Echavarren, A. M., J. Am. Chem. Soc.2005, 127, 6178.

68. Nieto-Oberhuber, C.; Munoz, M. P.; Lopez, S.; Jiménez-Nunez, E.;Nevado, C.; Herrero-Gomez, E.; Raducan, M.; Echavarren, A. M., Chem.Eur. J. 2006, 12, 1677.

69. Kisanga, P.; Widenhoefer, R. A., J. Am. Chem. Soc. 2000, 122, 10017.

70. Bei, X.; Hagemeyer, A.; Volpe, A.; Saxton, R.; Turner, H.; Guram, A.S., J. Org. Chem. 2004, 69, 8626.

71. Guram, A. S.; Bei, X.; Turner, H. W., Org. Lett. 2003, 5, 2485.

Myra Beaudoin Bertrand & John P. WolfeUniversity of Michigan, Ann Arbor, MI, USA

Bis(acetonitrile)[(1,2,5,6-ηηη)-1,5-cyclo-octadiene]-rhodium(1+),tetrafluoro-borate(1-)

Rh NCCH3

NCCH3

BF4

[32679-02-0] C12H18BF4N2Rh (MW 379.99)

(catalyst for the formation of C–C bonds between various organicelectrophiles and organometallic reagents. Also used as a catalyst

for hydroformylation and hydrogenation reactions)

Physical Data: mp 188–190 ◦C (dec).2

Solubility: soluble in most organic solvents; insoluble in H2O.Form Supplied in: yellow crystals, commercially available from

Aldrich (cat. #640360).Analysis of Reagent Purity: melting point, IR.2

Preparative Methods: can be prepared by reaction of[RhCl(cod)]2 and AgBF4 in CH2Cl2 and CH3CN, followed


BIS(ACETONITRILE)[(1,2,5,6-η)-1,5-CYCLOOCTADIENE]-RHODIUM(1+),TETRAFLUOROBORATE(1-) 13

by filtration, concentration of the reaction solution, and precip-itation of the product using Et2O.3 A similar synthesis has alsobeen performed using Ph3CBF4 instead of AgBF4.2

Purification: recrystallization can be done from acetonitrile withslow addition of diethyl ether.

Handling, Storage, and Precautions: store in a cool, dry placein a tightly sealed container. Handle and store under an inertatmosphere of nitrogen or argon. May cause mild to severe irri-tation of the eyes, skin, nose, mucous membrane, or respiratorytract. Avoid ingestion, inhalation, or direct contact with skin orclothing. The toxicological effects of this reagent have not beenthoroughly tested; unknown hazards may be present. Chemical-safety goggles and appropriate gloves are highly recommended.Use only in a chemical fume hood and near safety shower andeye bath. Do not breathe dust. Compound is incompatible withoxidizing agents and active metals and decomposes to carbondioxide, carbon monoxide, boron oxides, hydrogen fluoride,and rhodium salts.

1,2-Additions to Carbonyls. Bis(acetonitrile) (η4-1,5-cyclo-octadiene) rhodium(I) tetrafluoroborate has been shown by Oi tocatalyze addition of organometallic reagents to aldehydes. Un-der mild conditions, aromatic organostannanes undergo reactionwith aromatic and aliphatic aldehydes in the presence of 2 mol %catalyst to generate secondary alcohols in excellent yields (eq 1).4

Ar SnMe3O

HR Ar R

OH+

[Rh(cod)(MeCN)2]BF4

(2 mol %)

THF, 60 °C(1)

34–96%

Despite the fact that this reaction is not compatible withketones, �-dicarbonyl compounds also prove to be viable electro-philes.3 For example, under the same conditions as thoseemployed above, benzil treated with aryltrimethylstannanes in thepresence of [Rh(cod)(MeCN)2]BF4 provides the monoadditionproduct (eq 2). Glyoxylic acid esters as well as �-ketoesters arealso compatible under the reaction conditions.

Ar SnMe3

O

Ph

O

PhAr

OH

PhO

Ph+

[Rh(cod)(MeCN)2]BF4

(2 mol %)

THF, 60 °C

(2)

51–99%

As well as organostannanes, phenylmethyldifluorosilane hasbeen shown to add to aryl-, heteroaryl-, and alkyl-aldehydes in thepresence of KF using [Rh(cod)(MeCN)2]BF4 as catalyst (eq 3).5

Ph

OH

RSiMeF2Ph

O

HR+

[Rh(cod)(MeCN)2]BF4

(2 mol %)

KF (3 equiv), THF, 60 °C(3)

18–99%

1,2-Additions to Imines. The addition of organometallicreagents to imines is a useful method of synthesizing amines.[Rh(cod)(MeCN)2]BF4 has been employed in the arylation ofaldimines with N-electron-withdrawing groups. It was initially

shown that addition of organostannanes, providing the corres-ponding sulfonamines in good to excellent yields (eq 4).3,6,7 Inalmost concurrent reports Oi and Miyaura demonstrated that arylorganostannanes and sodium tetraphenylborate7 are viable coup-ling partners in additions to N-tosylimines. Also, arylmethyldiflu-orosilanes react in the presence of [Rh(cod)(MeCN)2]BF4 and KFto provide N-tosylamines.8

Ar SnMe3

N

H

R2

R1 R1

HNR2

Ar+

[Rh(cod)(MeCN)2]BF4

(2 mol %)

THF, 60 °C(4)

R1 = aryl, heteroaryl, COOEtR2 = tosyl, PO(OEt)2, COPh, COOtBu

48–98%

Subsequent reports have shown that boron-based couplingagents other than sodium tetraphenylborate can be employed inrhodium-catalyzed addition to imines.9 Miyaura has shown thatthe coupling of aryl boronic acids with N-sulfonylimines in thepresence of [Rh(cod)(MeCN)2]BF4 provides N-protected aminesin excellent yields (eq 5).

Ar

HNSO2Ph

R

B(OH)2ArN

HR

SO2Ph

+

1. [Rh(cod)(MeCN)2]BF4

(2 mol %)dioxanes, 95 °C

(5)

68–99%

2. H2O

Of particular note is the diastereoselective addition of arylboronic acids to sulfinimines in dioxanes and water.10 Batey hasshown that a range of aryl-, heteroaryl-, and alkyl-sulfinimineswill react with arylboronic acids with high diastereoselectivitiesunder rhodium(I) catalysis, which, following acidic hydrolysis,generate �-chiral primary amine salts (eq 6).

R

SON

H

Ar B(OH)2

R Ar

NH3Cl

1. [Rh(cod)(MeCN)2]BF4

(5 mol %)

Et3N (2 equiv)dioxanes/H2O, rt

(6)

44–99% yieldup to 98% de

+

2. MeOH/HCl, 1 h

1,4-Additions to Carbonyl-containing Compounds. Whencontrasted to the number of reports involving rhodium(I)-catalyzed 1,4-additions to carbonyl-containing compounds,11 theuse of [Rh(cod)(MeCN)2]BF4 as either the catalyst or as a pre-catalyst for generation of a chiral complex is somewhat limited.However, there remain selected examples where this catalyst is therhodium source of choice for conjugate addition to enones and re-lated species. For example, Miyaura has shown that phenylboronicacid will react with �,�-unsaturated aldehydes and estersin the presence of [Rh(cod)(MeCN)2]BF4, providing the 1,4-addition product in excellent yield (eq 7).12,13 This reaction canbe performed in the presence of (S)-BINAP, generating enantioen-riched products. However, neutral rhodium complexes were moreeffective catalysts in this reaction.

Aryl- and alkenylstannanes are also effective coupling part-ners in 1,4-additions to �,�-unsaturated carbonyl compounds with[Rh(cod)(MeCN)2]BF4 as catalyst.14,15 Oi has shown that a wide


14 BIS(ACETONITRILE)[(1,2,5,6-η)-1,5-CYCLOOCTADIENE]-RHODIUM(1+),TETRAFLUOROBORATE(1-)

range of unsaturated aldehydes, ketones, and esters are compatibleunder the mild reaction conditions (eq 8).

B(OH)2PhPh OMe

O

OMePh

OPh

[Rh(cod)(MeCN)2]BF4

(3 mol %)

MeOH/H2O

87%

+

(7)

R1 SnMe3R2 R3

O

R2 R3

R1 O

+

(8)

[Rh(cod)(MeCN)2]BF4

(2 mol %)

THF, 60 °C

R1 = aryl, alkenyl; R2 = alkyl, aryl, H; R3 = alkyl, O-alkyl, H

23–98%

The same group has also demonstrated that organosiloxaneswill perform conjugate addition to a number of �,�-unsaturatedcarbonyl compounds. While the initial studies generated racemicproducts,16 subsequent investigations have shown that using4 mol % [Rh(cod)(MeCN)2]BF4 with 6 mol % (S)-BINAP, aryl-and alkenylsiloxanes will perform highly asymmetric 1,4-additionto �,�-unsaturated ketones, esters, and amides (eq 9).17,18 Unsat-urated aldehydes and nitriles are compatible in the racemic ary-lation and alkenylation chemistry, but have not been shown to becompatible under asymmetric catalysis.

Si(OEt)3R1

O

R2 R3

O

R2 R3

R1

[Rh(cod)(MeCN)2]BF4

(4 mol %)(S)-BINAP (6 mol %)

R1 = aryl, alkenyl; R2 = alkyl, aryl, H; R3 = alkyl, O-alkyl, H

23–98% yield up to 99% ee

+

(9)

dioxanes/H2O, 90 °C

Additionally, alkenylzirconium reagents will undergo catalytic,asymmetric 1,4-addition to �,�-unsaturated ketones, catalyzedby [Rh(cod)(MeCN)2]BF4 in the presence of (S)-BINAP.19 Bothcyclic and acyclic ketones provide the substituted enone products,though enantioselectivities tend to be higher with cyclic species(eq 10).

This work has been elegantly exploited by Nicolaou in the syn-thesis of the spirocyclic system of Vannusal A.20 By trapping thein situ-generated rhodium(I) enolate with an aldehyde, the resultis an asymmetric three-component reaction of �,�-unsaturatedketones, alkenylzirconium reagents, and aldehydes through a1,4-addition/aldol reaction sequence (eq 11).

R1

ZrCp2ClO

R3R2

OR2

R1 R3

[Rh(cod)(MeCN)2]BF4

(5 mol %)

(10)

52–99% yield up to 99% ee

THF, rt+

(S)-BINAP (6 mol %)

R1 = aryl, alkenyl; R2 = alkyl, aryl, H; R3 = alkyl

ZrCp2ClC6H13

TBSO

O

H

O

O OHOTBS

C6H13

OMe

MeO O

O

C5H11

+(S)-BINAP (6 mol %)

52%

+

[Rh(cod)(MeCN)2]BF4

(5 mol %)

(11)THF, rt

Synthesis of Organosilanes. [Rh(cod)(MeCN)2]BF4 has alsobeen employed as a catalyst in the synthesis of silane organometa-llics from aryl halides and triethoxysilane.21 Organosilanes pro-vide a useful alternative to organoboron or organotin reagentsin cross-coupling reactions. Thus, the rhodium(I)-catalyzedreaction of triethoxysilane and aromatic iodides and bromidesprovides a useful route to prepare aryltriethoxysilanes (eq 12),which were previously shown to be viable substrates in asym-metric 1,4-addition to �,�-unsaturated carbonyl compounds. Thismethod has also been employed in the synthesis of 3,6-bis(trietho-xysilyl)carbazoles, toward the generation of mesoporousmaterials.22

H Si(OEt)3 XR

(EtO)3SiR

+

(12)

[Rh(cod)(MeCN)2]BF4

(3 mol %)

Et3N (3 equiv), DMF, 80 °C

70–90 %

Hydrogenation. [Rh(cod)(MeCN)2]BF4 has not been exten-sively used as a hydrogenation catalyst. In the original communi-cation of its synthesis, Green and co-workers demonstrated thatwhen 1,5-cyclooctadiene is employed as a hydrogenation sub-strate, it is monohydrogenated to generate cyclooctene. They alsodemonstrated that 1,3-cyclooctadiene is not hydrogenated at allby this catalyst.23 This metal complex, though, has been used as


BIS(ACETONITRILE)DICHLOROPALLADIUM(II) 15

a precursor for asymmetric hydrogenation in combination withchiral phosphines.24 For example, using silica gel-immobilized(S)-i-Pr-phox as a ligand in combination with [Rh(cod)(MeCN)2]-BF4, the hydrogenation of methyl (Z)-�-(acetamido)cinnamate isaccomplished in 97% yield with 93% enantioselectivity (eq 13).

(S)-i-Pr-phox (1.2 mol %)

Ph

CO2Me

NHAc

MeOH

Ph

CO2Me

NHAc(13)

97% yield93% ee

[Rh(cod)(MeCN)2]BF4

(1 mol %)

H2 (2 atm)

Hydroformylation. [Rh(cod)(MeCN)2]BF4 itself has notbeen employed as a catalyst for hydroformylation. However,in combination with phosphine ligands, it has been shown tobe effective in the hydroformylation of styrene using a solid-supported catalyst.25 For example, a silica-supported diphe-nylphosphinoethane-derived phosphine in combination with[Rh(cod)(MeCN)2]BF4 catalyzes the hydroformylation of styreneand has been employed in mechanistic studies thereof.

Cycloisomerization. Interestingly, [Rh(cod)(MeCN)2]BF4

enables cycloisomerization of allyl propargyl ethers directly intosubstituted furans in one step (eq 14).26 This reaction was foundto be enhanced in the presence of catalytic quantities of carboxylicacids, for example, acetic acid. While the report reveals little func-tional group compatibility, it demonstrates a potential for use ofrelated cycloisomerizations to other heterocyclic targets, such aspyrroles.

OR2

R1

O

R1

R2

[Rh(cod)(MeCN)2]BF4

(2 mol %)dppp (6 mol %)

20–64%

(14)

R1 = alkyl; R2 = alkyl, aryl

dioxanes, 100 °C

Related Reagents. Other related rhodium compounds [usu-ally Rh(I)] include [Rh(cod)2]BF4, [RhCl(cod)]2, Rh/C,RhCl3, [Rh(OAc)2]2, Rh(acac)(CH2CH2)2, Rh(CO)2(acac),[RhCl(cod)]2, RhH(CO)(PPh3)3, RhCl(CO)(PPh3)2, RhI(PPh3)3,RhBr(PPh3)3, RhCl(PPh3)3, Rh(acac)(coe)2, Rh2(OAc)2.

1. Fagnou, K.; Lautens, M., Chem. Rev. 2003, 103, 169.

2. Green, M.; Kuc, T. A.; Taylor, S. H., J. Chem Soc. (A) 1971, 2334.

3. Oi, S.; Moro, M.; Fukuhara, H.; Kawanishi, T.; Inoue, Y., Tetrahedron2003, 59, 4351.

4. Oi, S.; Moro, M.; Inoue, Y., Chem. Commun. 1997, 1621.

5. Oi, S.; Moro, M.; Inoue, Y., Organometallics 2001, 20, 1036.

6. Oi, S.; Moro, M.; Fukuhara, H.; Kawanishi, T.; Inoue, Y., TetrahedronLett. 1999, 40, 9259.

7. Ueda, M.; Miyaura, N., J. Organomet. Chem. 2000, 595, 31.

8. Oi, S.; Moro, M.; Kawanishi, T.; Inoue, Y., Tetrahedron Lett. 2005, 45,4855.

9. Ueda, M.; Saito, A.; Miyaura, N., Synlett 2000, 11, 1637.

10. Bolshan, Y.; Batey, R. A., Org. Lett. 2005, 7, 1481.

11. Hayashi, T.; Yamasaki, K., Chem. Rev. 2003, 103, 2829.

12. Ueda, M.; Miyaura, N., J. Org. Chem. 2000, 65, 4450.

13. Sakuma, S.; Sakai, M.; Itooka, R.; Miyaura, N., J. Org. Chem. 2000, 65,5951.

14. Oi, S.; Moro, M.; Ono, S.; Inoue, Y., Chem. Lett. 1998, 83.

15. Oi, S.; Moro, M.; Ito, H.; Honma, Y.; Miyano, S.; Inoue, Y., Tetrahedron2002, 58, 91.

16. Oi, S.; Honma, Y.; Inoue, Y., Org. Lett. 2002, 4, 667.

17. Oi, S.; Taira, A.; Honma, Y.; Inoue, Y., Org. Lett. 2003, 5, 97.

18. Oi, S.; Taira, A.; Honma, Y.; Sato, T.; Inoue, Y., Tetrahedron: Asymmetry2006, 17, 598.

19. Oi, S.; Sato, T.; Inoue, Y., Tetrahedron Lett. 2004, 45, 5051.

20. Nicolaou, K. C.; Tang, W.; Dagneau, P.; Faraoni, R., Angew. Chem. Int.Ed. 2005, 44, 3874.

21. Murata, M.; Ishikura, M.; Nagata, M.; Watanabe, S.; Masuda, Y., Org.Lett. 2002, 4, 1843.

22. Maegawa, Y.; Goto, Y.; Inagaki, S.; Shimada, T., Tetrahedron Lett. 2006,47, 6957.

23. Green, M.; Kuc, T. A.; Taylor, S. H., J. Chem Soc., Chem. Commun.1970, 1553.

24. Aoki, K.; Shimada, T.; Hayashi, T., Tetrahedron: Asymmetry 2004, 15,1771.

25. Collman, J. P.; Belmont, J. A.; Brauman, J. I., J. Am. Chem. Soc. 1983,105, 7288.

26. Kawai, H.; Oi, S.; Inoue, Y., Heterocycles 2006, 67, 101.

Daniel A. Black & Keith FagnouUniversity of Ottawa, Ottawa, Ontario, Canada

Bis(acetonitrile)dichloropalladium(II)

PdNCl

N Cl

C CH3

CH3C

[14592-56-4] C4H6Cl2N2Pd (MW 259.43)Main Applications:

• PdII-catalyzed oxidative functionalization of alkenes,alkynes, and related unsaturated compounds.

• PdII-catalyzed sigmatropic rearrangements.

• Precursor of Pd0 catalyst in a wide array of cross-couplingreactions.

• Precursor of other PdII dichloride complexes by acetonitrileligand exchange.

Physical Data: mp 129–131 ◦C (decomp).Solubility: sol CH2Cl2, THF, acetone, CH2Cl2/CH3CN. Insol

water and aqueous solutions.Form Supplied in: orange solid; commercially available.Preparation and Purification: PdCl2(CH3CN)2 is easily prepared

by stirring PdCl2 in CH3CN at room temperature for 24 h(or 18 h at reflux) under nitrogen. The resulting orange solidis filtered, washed with Et2O, and dried. The dried productcan be used without further purification. Recrystallizationfrom CH3CN/CH2Cl2/hexane or CH3CN/Et2O gives PdCl2(CH3CN)2 as bright yellow crystals.


16 BIS(ACETONITRILE)DICHLOROPALLADIUM(II)

Handling, Storage, and Precautions: This complex, kept in aclosed vessel is stable for months at room temperature. PdCl2(CH3CN)2 is harmful by inhalation, in contact with skin andif swallowed.

General Considerations. The ability of palladium to act bothas a nucleophilic (Pd0) and electrophilic (PdII) catalyst has madepalladium chemistry an indispensable tool for synthetic organicchemists.1 Pd0-catalysis has dominated the landscape of cata-lyst development for the past several decades. In particular, Pd-catalyzed cross-coupling reactions are among the most efficientcarbon–carbon and carbon–heteroatom bond-forming reactionsin organic synthesis.2 Although to a lesser extent, PdII oxidationcatalysis has also experienced great development, leading to syn-thetically useful protocols and providing organometallic chemistswith a platform to investigate fundamental processes.3 In con-trast to Pd0-catalysis, in PdII-catalyzed oxidation reactions thefunctionalization of the organic substrate occurs with concomitantreduction of PdII to Pd0, which requires the in situ oxidation ofPd0 back to PdII to make the reaction catalytic with respect to PdII.Inorganic oxidants (such as CuII salts, HNO3, H2O2) or MnO2,and organic compounds (such as benzoquinone or alkyl hydroper-oxides) are typically used for regenerating the active PdII species.More recently efficient reoxidation of Pd0 with molecular oxygen,the most practical oxidant, has been achieved in DMSO.4 It wasfound that DMSO, which is a favorable ligand for Pd0, promotesdirect oxidation to PdII with O2. This and other recent achieve-ments in this field have led to a re-emergence of PdII-catalyzedoxidation chemistry.

Palladium(II) compounds such as PdCl2, Pd(OAc)2, orPd(acac)2 are stable and commercially available. PdCl2 has lowsolubility in water and organic solvents, but it becomes solublein organic solvents by forming solvates such as PdCl2(CH3CN)2

or PdCl2 (PhCN)2. They can be used in two important ways: asunique oxidizing agents and as sources of Pd0 catalysts. StablePdII salts are easily reduced to Pd0 complexes with several reduc-ing agents such as phosphines, metal hydrides, or organometallicreagents. In contrast to Pd0-chemistry, which is dominated by the

use of phosphanes and other soft donor ligands to stabilize Pd0

species, most of these ligands decompose rapidly under oxidizingreaction conditions required in most PdII-catalyzed processes, andtherefore palladium oxidation chemistry has been dominated bythe use of simple palladium salts.

Palladium(II)-Catalyzed/Promoted Addition of Nucleo-philes across the C=C Bond of Alkenes. Fast and reversiblecoordination of electrophilic PdII complexes to alkenes produces�-complexes that are activated toward addition of heteroatom-and carbon-nucleophiles. The nucleophilic attack on the �-olefinspecies is called palladation and generally occurs anti to the metal(trans-heteropalladation or carbopalladation) at the more substi-tuted vinylic carbon, to give a �-alkylpalladium(II) complex thatis usually unstable and may then undergo a variety of processes(eq 1). Depending on the reaction conditions this PdII interme-diate can evolve by a palladium �-hydride elimination (path a),resulting in nucleophilic substitution of the olefinic proton, ordisplacement of the Pd by another nucleophile (path b) to giveformally the nucleophilic addition product. Another possibility istransmetallation with other organometallic reagents followed byreductive elimination (path c), or various insertion processes tothe �-alkylpalladium species, such as carbon monoxide insertionfollowed by alcoholysis of the resulting acylpalladium interme-diate (path d). In all these transformations, the oxidation of theorganic substrate occurs with concomitant reduction of PdII toPd0, therefore consuming a stoichiometric amount of expensivePdII salts. Sometimes, but not always, the reduced Pd0 can be re-oxidized in situ to PdII, making feasible the development of a trulyuseful synthetic method catalytic with regard to PdII. Typical PdII

salts known to promote Lewis acid activation of alkenes, allowingthe nucleophilic addition, are PdCl2, Pd(OAc)2, PdCl2(CH3CN)2,PdCl2(PhCN)2, and M2PdCl4 (M = Li, Na), the latter used espe-cially for aqueous or alcohol reaction media.

After palladation of the alkene, the �-alkylpalladium(II) com-plex intermediate may also evolve to form other PdII species. Insuch a case, no reoxidant is required for efficient catalyticreaction. An important PdII-generation step in PdII-catalyzedreactions is the elimination of heteroatom groups such as Cl, Br,OAc, and OH at the �-position to palladium (eq 2), which is faster

R1

Nu

Pd-XH

R1

Nu

COPdX

R1

H

R1

Nu

B

R1

Nu

B

R1

Nu

CO2R3

R1

Nu

Pd-R2R′

Nu

R2

CO

HXNu

Pd0+

R2-M

Pd0+

Pd0+R3-OH

Pd0+

(a)

(c)

(b)

(d)

palladationPdX2

(1)


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